PROJECT SUMMARY/ABSTRACT Inflammation appears to play a critical role in the formation of cerebral aneurysms, their progression to rupture- prone type, and ultimately to rupture. Evidence supporting this hypothesis includes recent data from human neurosurgery patients and experimental animal models demonstrating that aneurysm wall tissue is rich with macrophages and inflammatory molecules. To investigate potential therapeutic implications of this hypothesis, I carried out a retrospective study examining whether patients with unruptured cerebral aneurysms who took aspirin had a reduced risk of aneurysm rupture. This study was performed using the International Study of Unruptured Intracranial Aneurysms data base. Patients who used aspirin three times weekly to daily had a significantly decreased risk of aneurysm rupture. My current scientific goals, and the subject of this proposal, are to study the molecular mechanisms by which inflammation influences cerebral aneurysm formation and rupture. I am using the well-established Hashimoto mouse aneurysm model to pursue two specific aims. In Specific Aim 1, I will determine the contributions of COX-1 and COX-2 to the protective effect of aspirin against aneurysm rupture. In Specific Aim 2, I will determine the cell type associated with activation of the COX-2 pathway resulting in a protective effect against aneurysm rupture. These studies will involve the use of complementary genetic, pharmacological and bone marrow transplantation experimental approaches. Knowledge of the inflammation related molecular mechanisms of aneurysm formation and rupture will provide information that is critical to the development of effective new medical therapies for patients with this dangerous cerebrovascular disease.